Synthetic cannabinoids

Bag and contents of a well known early "brand" named "Spice" that contains synthetic cannabinoids, now illegal throughout much of the world.

Synthetic cannabinoids are designer drugs that are chemically different from the chemicals in cannabis but which are sold with claims that they give the effects of cannabis. When these chemicals are sprayed or otherwise soaked into a base material which is often plant-based, then the plant with chemicals is sometimes misleadingly called synthetic marijuana.[1] These products are sold for recreational drug use.[1]

There are several psychoactive artificial cannabinoid families (e.g. AM-xxx, HU-xxx, JWH-xxx, CP xx) that are sold under brand names like K2,[2]Spice,[3] and Spike[4] both of which are now used as generic terms used for any synthetic cannabinoid product.

When synthetic cannabinoid blends first went on sale in the early 2000s, it was thought that they achieved an effect through a mixture of natural herbs. Laboratory analysis in 2008 showed that this was not the case, and that they in fact contain synthetic cannabinoids that act on the body in a similar way to cannabinoids naturally found in cannabis, such as THC. A large and complex variety of synthetic cannabinoids, most often cannabicyclohexanol, JWH-018, JWH-073, or HU-210, are used in an attempt to avoid the laws that make cannabis illegal, making synthetic cannabinoid a designer drug. They have been sold under various brand names, online, in head shops, and other stores. Studies have associated synthetic cannabinoid use with psychotic episodes days after use, some of which have resulted in death.[5]

They are often marketed as herbal incense or "herbal smoking blends", and the products are usually consumed through smoking. Although synthetic cannabinoids may not produce positive results in drug tests for cannabis, it is possible to detect their metabolites in human urine. The synthetic cannabinoids contained in these products have been made illegal in many countries.

Synthetic cannabinoids are used for recreational drug use,[1] however many were designed for research purposes, in part due to legal restrictions on natural cannabinoids preventing research. Studies are ongoing to examine their therapeutic potential.[6][7][8] One study found that while mice developed withdrawal symptoms from THC, that was not the case with the synthetic cannabinoid AM-1710, which was able to relieve neuropathic pain, but without inducing either tolerance or withdrawal, suggesting that CB2 receptors could be a viable target for development of pain-management drugs that avoid adverse outcomes of cannabis use.[9]

The drug is used in an attempt to get the effects of cannabis or similar effects.[10] Part of the appeal of the drug is that it is marketed as being like natural cannabis.[10] In comparison with cannabis, it is inexpensive and can be easy to get as a commercial product through convenience stores, tobacco shops, or head shops.[10] A standard drug test will not identify a user of synthetic cannabis whereas that would happen with natural cannabis.[10] Synthetic cannabinoids have been legal in the past, or at least, not illegal to sell or possess.[10] There are many different chemicals which are called "synthetic cannabinoids" and many of them are regulated by different laws or not mentioned in laws.[10]

Synthetic cannabinoids frequently produce adverse effects which lead to hospitalization or referrals to poison control centers.[10][11] Synthetic cannabinoids can be any of a number of different drugs, each with different effects.[10] There is no way to describe general effects among all the different chemicals because they all have different effects.[10] Also, each chemical will have different effects at different dosages, but because the drugs are crudely manufactured, it is not possible to know what chemicals the drugs contain or how much of any chemical one is taking.[10]

Although most synthetic cannabinoids exhibit only the typical cannabinoid effects when used at appropriate doses, they are potent drugs capable of causing clinical intoxication and death (probably due to CNS depression and hypothermia) when used inappropriately. Many compounds have been banned in the U.S. and numerous other countries, although loopholes remain and new examples continue to be encountered on a regular basis.[12][13]

No official studies have been conducted on the effects of synthetic cannabinoids on humans (as is often the case with illegal and potentially toxic compounds).[14] However, reports describing effects seen in patients seeking medical care after taking synthetic cannabinoids have been published. Compared to cannabis and its active cannabinoidTHC, the adverse effects are often much more severe and can include hypertension, tachycardia, myocardial infarction,[15] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[16] and panic attacks.[17][18][19][20][21] Among individuals who need emergency treatment after using synthetic cannabis, the most common symptoms are accelerated heartbeat, high blood pressure, nausea, blurred vision, hallucination and agitation.[22] Other symptoms included epileptic seizures, and acute psychosis.[22]

At least one death has been linked to overdose of synthetic cannabinoids[23] and in Colorado three deaths in September 2013 have been investigated for being linked to synthetic cannabinoids.[24]

These more severe adverse effects in contrast to use of marijuana are thought to stem from the fact that many of the synthetic cannabinoids are full agonists to the cannabinoid receptors, CB1R and CB2R, compared to THC which is only a partial agonist and thus not able to saturate and activate all of the receptor population regardless of dose and resulting concentration.[25] It has also been seen that phase 1 metabolism of JWH-018 results in at least nine monohydroxylated metabolites and with at least three of the metabolites shown to have full agonistic effect on CB1R, which, compared to metabolism of THC, only results in one psychoactive monohydroxylated metabolite. This may further explain the increased toxicity of synthetic cannabinoids compared to THC.[23]

Professor John W. Huffman, who first synthesised many of the cannabinoids used in synthetic cannabis, is quoted as saying, "People who use it are idiots.[14] You don't know what it's going to do to you."[26] A user who consumed 3 g of Spice Gold every day for several months showed withdrawal symptoms, similar to those associated with withdrawing from the use of narcotics. Doctors treating the user also noted that his use of the product showed signs associated with addiction.[27] One case has been reported wherein a user, who had previously suffered from cannabis-induced recurrent psychotic episodes, suffered reactivation of his symptoms after using Spice. Psychiatrists treating him have suggested that the lack of an antipsychotic chemical, similar to cannabidiol found in natural cannabis, may make synthetic cannabis more likely to induce psychosis than natural cannabis.[28]

Studies are currently available which suggest an association between synthetic cannabinoids and psychosis.[29] The use of synthetic cannabinoids can be associated with psychosis and physicians are beginning to investigate possible use of synthetic cannabinoids in patients with inexplicable psychotic symptoms. In contrast to most other recreational drugs, the dramatic psychotic state induced by use of synthetic cannabinoids has been reported, in multiple cases, to persist for several weeks, and in one case for seven months, after complete cessation of drug use.[30] Individuals with risk factors for psychotic disorders are often counseled against using synthetic cannabinoids.[31]

Synthetic cannabis consumption does not cause a positive urine drug test for THC, its metabolites or other cannabinoids present in marijuana using standard immunological screening procedures, GC-MS-screening, or multi-target screening by LC-MS/MS.[27][32] Serum concentrations of the chemicals present in synthetic cannabis are generally in the 1–10 μg/L range during the first few hours after recreational usage. The major urinary metabolites, in most cases formed by oxidation of the alkyl side-chain to an alcohol and carboxylic acid followed by glucuronide conjugation, but also by N-dealkylation and aromatic hydroxylation, are usually present in urine at similar concentrations. The presence of synthetic cannabinoids or their metabolites in biofluids may be determined using specifically-targeted commercially available immunoassay screening methods, while liquid chromatography-mass spectrometry is most often used for confirmation and quantitation.[33][34][35][36][37]

There is controversy about calling this substance Spice or K2 or synthetic marijuana. "Synthetic marijuana" is a misnomer according to Dr. Lewis Nelson, a medical toxicologist at the NYU School of Medicine who states they are "really quite different, and the effects are much more unpredictable. It's dangerous".[38] Since the term synthetic does not apply to the plant but rather to the chemical that the plant contains (tetrahydrocannabinol), the term synthetic cannabinoid is more appropriate.[39] Research on the safety of synthetic cannabinoids is now becoming available. Initial studies are focused on the role of synthetic cannabinoids in psychosis. Synthetic cannabinoids may precipitate psychosis and in some cases it may be prolonged. Some studies suggest that synthetic cannabinoid intoxication is associated with acute psychosis, worsening of previously stable psychotic disorders, and it may trigger a chronic (long-term) psychotic disorder among vulnerable individuals such as those with a family history of mental illness.[40][41] Synthetic cannabis is stated to be toxic and addictive to the brain.[42]

Synthetic cannabis is claimed by the manufacturers to contain a mixture of traditionally used medicinal herbs, each of which producing mild effects, with the overall blend resulting in the cannabis-like intoxication produced by the product. Herbs listed on the packaging of Spice include Canavalia maritima (coastal jack-bean), Nymphaea caerulea (blue Egyptian water lily), Scutellaria nana (dwarf skullcap), Pedicularis densiflora (Indian warrior), Leonotis leonurus (lion's tail), Zornia latifolia (maconha brava), Nelumbo nucifera (lotus), and Leonurus sibiricus (honeyweed). However, when the product was analyzed by laboratories in Germany and elsewhere, it was found that many of the characteristic "fingerprint" molecules expected to be present from the claimed plant ingredients were not present. There were also large amounts of synthetic tocopherol present. This suggested that the actual ingredients might not have been the same as those listed on the packet, and a German government risk assessment of the product conducted in November 2008 concluded that it was unclear as to what the actual plant ingredients were, where the synthetic tocopherol had come from, and whether the subjective cannabis-like effects were actually produced by any of the claimed plant ingredients or instead caused by a synthetic cannabinoid drug.

The first synthetic cannabinoids were synthesized by Roger Adams in the early 1940s. Early cannabinoid research concentrated on tetrahydrocannabinol or "THC" as the main psychoactive and analgesic compound found in the cannabis plant. Other naturally cannabinoids such as cannabidiol or "CBD" are less well studied, and not illegal in most jurisdictions. Most synthetic cannabinoids are analogs of THC.

The first generation of THC analogs (synhexyl, nabilone, nabitan, nantradol) featured slight variations of the THC molecule, such as esterifying the phenolic hydroxy group, extending and branching of the pentyl side chain, or substituting nitrogen for oxygen in the benzopyran ring.[48] These analogs can be grouped into classical (HU-210), bicyclic (CP-55,940), and tricyclic (CP-55,244). Tritium-labelled cannabinoids such as [³H]CP-55,940 were instrumental in discovering the cannabinoid receptors in the early 1990s.[49]

Nabilone entered the clinic in 1981 as an antiemetic. Synthetic THC (marinol, dronabinol) entered the clinic in 1985 as an antiemetic and again in 1991 as an appetite stimulant.[50]

HU-210 is apparently the most active cannabinoid used at present. It is up to 800 times more active than THC in mice. AM-404 (a paracetamol metabolite) is an inhibitor of endocannabinoid cellular uptake, prolonging their effects.[51]Nabitan, O-1057 and TMA are water-soluble.

In July 2010, it was announced that JWH-018 is one of the active components in at least three versions of Spice, which had been sold in a number of countries around the world since 2002, often marketed as incense.[56][57][58][59] Another potent synthetic cannabinoid, HU-210, has been reported to have been found in Spice seized by U.S. Customs and Border Protection.[60] An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073.[61]

Different ratios of JWH-018 and CP 47,497 and their analogues have been found in different brands of synthetic cannabis[32] and manufacturers constantly change the composition of their products.[62] The amount of JWH-018 in Spice has been found to vary from 0.2% to 3%.[63]

Other non-cannabinoid ingredients have also been found in synthetic cannabis blends around the world, but they do not produce classical cannabis intoxication effects. This includes substituted cathinone derived stimulant drugs such as 4-methylbuphedrone and 4-methyl-alpha-PPP, and psychedelic tryptamine derivatives such as 4-HO-DET.[64][65] In 2013, a designer opioid drug, AH-7921, was detected in smoking blends in Japan, along with several novel cannabinoids and a cathinone analogue.[66]

According to the Psychonaut Web Mapping Research Project, synthetic cannabis products, sold under the brand name Spice, first appeared in Europe in 2004.[67] The brand "Spice" was released in 2004 by the now-dormant company The Psyche Deli in London, UK. In 2006 the brand gained popularity. According to the Financial Times, the assets of The Psyche Deli rose from £65,000 in 2006 to £899,000 in 2007.[68] The EMCDDA[clarification needed] reported in 2009 that Spice products were identified in 21 of the 30 participating countries. Because Spice was the dominant brand until 2009, the competing brands that started to appear from 2008 on were also dubbed Spice. Spice can, therefore, refer to both the brand Spice, as to all herbal blends with synthetic cannabinoids added.

In 2009 a survey of readers of a popular English magazine Mixmag found that one in eight respondents had used synthetic cannabis, compared to 85% who had used cannabis.[69]

According to a 2012 US Federal Bureau of Investigation memo which mentions a group of five synthetic chemicals made temporarily illegal by the US Drug enforcement Agency the year before, the term for naming this compound is either herbal incense or synthetic marijuana. The memo suggests that Dr. John W. Huffman, an organic chemist at Clemson University, was responsible for the development of the first synthetic marijuana (JWH-018) created as a part of his groundbreaking research on cannabinoid receptors in the human brain. The FBI concludes that as a result of the publication of his research people searching for a "marijuana-like-high" would follow Dr Huffman's recipes and methods.[70]

In addition to synthetic marijuana, K2 and Spice, other brand names include Black Mamba, Bombay Blue, Genie, and Zohai.[71] According to Partnership at Drugfree.org, other names also include Bliss.[72] The drug is also known as "synthetic cannabinoid receptor agonists".

the Austrian Ministry of Health announced on December 18, 2008 that Spice would be controlled under Paragraph 78 of their drug law on the grounds that it contains an active substance that affects the functions of the body, and the legality of JWH-018 is under review.[73][74][75]

Germany

JWH-018, CP 47,497 and the C6, C8 and C9 homologues of CP 47,497 have been illegal in Germany since January 22, 2009.[54][76]

Finland

Spice blends are classified as a medicine in Finland, and, therefore, it is illegal to order them without a prescription. In practice, it is not possible to get a prescription.[citation needed]

France

JWH-018, CP 47,497 (and its homologues) and HU-210 were all made illegal in France on February 24, 2009.[77]

Ireland

from June 2010, JWH-018, along with a variety of other designer drugs, has been illegal.[78]

Latvia

JWH-018, JWH-073, CP 47,497 (and its homologues) and HU-210 as well as leonotis leonurus have been all banned in Latvia since 2005.[79] After the first confirmed lethal case from the use of legal drugs in late 2013, parliament significantly increased the number of temporarily banned substances used in Spice and similar preparations. On April 3, 2014, parliament made selling of the temporarily banned substances a criminal offence.[80]

on April 9, 2009, the Chief Medical Officer of the Russian Federation issued a resolution on reinforcing control over the sales of smoking blends. These blends, marketed under the trade names AM-HI-CO, Dream, Spice (Gold, Diamond), Zoom, Ex-ses, Yucatán Fire and others, have been declared to contain Salvia divinorum, Hawaiian wood rose, and blue lotus, and are prohibited to be sold. These substances have been found to have "psychotropic, narcotic effects, contain poisonous components and represent potential threat for humans". The resolution does not mention JWH-018 or other synthetic cannabinoids.[86] On January 14, 2010, the Russian government issued a statement including 23 synthetic cannabinoids found in smoking blends Hawaiian Rose and Blue Lotus on the list of prohibited narcotic and psychotropic substances.[87]

About 780 new psychoactive substances were added to the list from 2011 to 2014. The drugmakers avoided all the bans by making slight changes to the drugs. In the autumn of 2014, more than two-thousand Spice consumers in Russia sought medical attention, one-thousand were admitted to hospitals, and 40 people died[88] On October 30, 2014, President Vladimir Putin brought in a bill that would ban the turnover of any type of smoking blends and introduce administrative sanctions and criminal responsibility for it.[89]

Slovakia

Spice is legal in Slovakia. The National Anti-Drug Unit is considering adding it to the list of controlled substances.[90] The latest anti-drug law version (468/2009) valid since January 2010 does not mention active compounds of Spice.[91]

Spain

Spice is unregulated in Spain. For this reason, Spice is available in grow shop stores or cannabis related stores, and it can be bought and shipped online without any legal impediment from those kind of stores.[92] However, as Spanish law permits growing up to two cannabis plants per household, and the possession and consumption of cannabis on private property is also legal, cannabis alternatives like Spice are largely redundant and thus remain relatively unknown in Spain.[93]

Sweden

CP 47,497-C6, CP 47,497-C7, CP 47,497-C8, CP 47,497-C9, JWH-018, JWH-073 and HU-210 were all made illegal in Sweden on September 15, 2009. The bill was accepted on July 30, 2009 and was put in effect on September 15, 2009.[94]

Spice, which is colloquially called bonzai in Turkey, was added to the list of drugs and psychotropic substances in 07.01.2011 by the law which numbered as 2011/1310 B.K.K. (February 13, 2011 and the Official Gazette No. 27845)[96]

United Kingdom

Many cannabinoids were legal in the United Kingdom until December 2009, when they were classified as a Class B drugs.[97] The UK has continued to ban new synthetic cannabinoids as they come to market but they are typically replaced instantly by novel alternatives.

on June 17, 2011, the Western Australian government banned all of the synthetic cannabinoids found in already existing products, including brands such as Kronic, Kalma, Voodoo, Kaos, and Mango Kush. Western Australia was the first state in Australia to prohibit the sale of certain synthetic cannabinoids.[101][102] On June 18, 2013, an interim ban made a large list of product brands and synthetic substances illegal to sell anywhere in Australia.[103] This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[104] Synthetic cannabis remains illegal in NSW, where a bill was passed on September 18, 2013, that bans entire families of synthetic drugs instead of only banning existing compounds that have been identified.[105][106] The introduction of this law makes NSW the first state in Australia to completely ban substances with psychoactive properties.[106]

New Zealand

Spice is illegal in New Zealand, it is classified as a Class C controlled drug.[107] The New Zealand Parliament passed a law in July 2013 banning the sale of legal highs in dairies and supermarkets, but allowing some "low risk" drugs to continue to be sold through speciality licensed shops.[108] Synthetic cannabinoids, as well as all other legal highs were outlawed at midnight on 7 May 2014, after a law was passed a week prior by the New Zealand government.[109]

The case of David Mitchell Rozga, an American teenager from Indianola, Iowa, brought international attention to K2. Rozga shot himself in the head with a family owned hunting rifle in an apparent suicide in June 6, 2010. After news of Rozga's death, it was reported by friends that they had smoked K2 with Rozga approximately one hour before his death. The nature of his death and reports from numerous family members, had led investigators to suspect that it was likely Rozga was under the influence of a mind-altering substance, at the time of his death. The death of Rozga has been used as a face of political lobbying against the continuation of K2, and other legal synthetic drugs, such as bath salts.

Prior to that, some compounds within synthetic cannabis (HU-210) were scheduled in the US under federal law, while others (JWH-073) have been temporarily scheduled until final determination of their status can be made.[119][120][121][122] The Drug Enforcement Administration (DEA) considers it to be a "drug of concern",[123] citing "...a surge in emergency-room visits and calls to poison-control centers. Adverse health effects associated with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure."[124][125]

Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[126]Georgia and Alabama in May 2010,[127][128]Tennessee and Missouri in July 2010,[129][130]Louisiana in August 2010,[citation needed]Mississippi in September 2010,[citation needed] and Iowa.[131] An emergency order was passed in Arkansas in July 2010 banning the sale of synthetic cannabis.[132] In October 2010, the Oregon Board of Pharmacy listed synthetic cannabinoid chemicals on its Schedule 1 of controlled substance, which means that the sale and possession of these substances is illegal under the Oregon Uniform Controlled Substances Act.[133] According to the National Conference of State Legislatures, several other states are also considering legislation, including New Jersey, New York, Florida, and Ohio.[130] Illinois passed a law on July 27, 2010 banning all synthetic cannabinoids that goes into effect January 1, 2011.[134] Michigan banned synthetic cannabinoids in October 2010,[135] and the South DakotaLegislature passed a ban on these products which was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate effect under an emergency clause of the state constitution).[136]Indiana banned synthetic cannabinoids in a law which became effective in March 2012.[137]North Carolina banned synthetic cannabis by a unanimous vote of the state senate, due to concerns that its contents and effects are reasonably similar to natural cannabis, and may cause equal effects in terms of psychological dependency.[138][139]

Following cases in Japan involving the use of synthetic cannabis by navy, army and marine corps personnel resulted in the official banning of it,[140] a punitive general order issued on January 4, 2010 by the Commander Marine Corps Forces, Pacific prohibits the actual or attempted possession, use, sale, distribution and manufacture of synthetic cannabis as well as any derivative, analogue or variant of it.[141] On June 8, 2010, the US Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering substance except alcohol or tobacco, among its service members.[142]

On November 24, 2010, the DEA announced that it would make JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol, which are often found in synthetic cannabis, illegal using emergency powers.[143] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[144][145] The temporary ban, for at least a year, came into effect on March 1, 2011.[146]

^Raphael Mechoulam; Lumir Hanuš (2004), "The cannabinoid system: from the point of view of a chemist", in David Castle; Robin Murray, Marijuana and Madness: Psychiatry and Neurobiology, Cambridge University Press, pp. 1–18

^Iowa Code § 124.204(4)(u)(PDF) (defining a Schedule I controlled substance to include "synthetic equivalents of the substances contained in the cannabis plant, or in the resinous extractives of such plant, and synthetic substances, derivatives, and their isomers with similar chemical structure and pharmacological activity to those substances contained in the plant....")